The present invention relates to novel methods of treatment and compositions employed in such methods of treatment. The present invention particularly relates to novel methods for preventing or treating gastrointestinal inflammatory diseases.
Most particularly, the present invention relates to the surprising and unexpected cytoprotective effects of pharmacological agents heretofore known to be useful only for other actions on the gastrointestinal tract.
Certain pharmacological agents have heretofore been known to be useful in exerting a cytoprotective effect on the gastrointestinal tract. This cytoprotective effect is manifest in the ability of such compounds to treat or prevent non-traumatically-induced, non-neoplastic inflammatory diseases of the gastrointestinal tract. References describing such cytoprotective effects of prostaglandins are U.S. Pat. No. 4,083,998 (Robert, "Treatment of Inflammatory Diseases of the Mammalian large Intestine with Cytoprotective Prostaglandins"), issued Apr. 11, 1978, U.S. Pat. No. 4,081,553 (Robert, "Cytoprotective Prostaglandins for Use in Intestinal Diseases"), issued Mar. 28, 1978, and U.S. Pat. No. 4,097,603 (Robert, "Gastric Cytoprotection with Non-Antisecretory Doses of Prostaglandins"), issued June 27, 1978.
As indicated in the patents described above, gastrointestinal inflammatory diseases include gastric inflammatory diseases (such as gastric ulcer, duodenal ulcer and gastritis), and intestinal inflammatory diseases (including Crohn's disease, inflammatory bowel disease, tropical and non-tropical sprue, infectious enteritis, colitis, ulcerative colitis, pseudomembranous colitis, diverticulitis, and allergenic and radiological inflammatory diseases).
As is known in the art, gastrointestinal inflammatory diseases are characterized by inflammation, specifically by the presence of edema, characteristic inflammatory cells (i.e., leucocytes, histiocytes, and macrophages), and, in some cases, necrosis and ulceration of the surface epithelium. These inflammatory diseases are known to be caused by a wide variety of agents present in the gastrointestinal tract which are known to attack the surfaces thereof, producing the inflammatory disease response. Such agents include microorganisms (viruses and fungii), bacterial toxins, certain pharmaceutical agents (antibiotics and anti-inflammatory steroids), and chemical agents (bile salts, toxic household chemicals). Indeed, gastric acid itself is capable of attacking the stomach lining and producing the inflammatory state.
The prostaglandins and related fatty acid metabolites are a class of compounds from which most if not all the known cytoprotective agents are derived. Indeed, the endogenous production of prostaglandins by cells of the gastrointestinal tract apparently represents at least a part of a natural cytoprotective mechanism. For example, when a non-steroidal anti-inflammatory compound (NOSAC) is administered to a mammal, one effect is the inhibition of prostaglandin biosynthesis in the gastrointestinal tract, resulting in gastritis and gastrointestinal blood loss. However, when a prostaglandin is administered together with the non-steroidal anti-inflammatory compound, the untoward gastrointestinal consequences of NOSAC administration are alleviated. See U.S. Pat. No. 3,927,213 (Lippman, "Prostaglandin E.sub.2 and Derivatives for Reducing the Side Effects of Anti-inflammatory Agents"), issued Dec. 16, 1975, and U.S. Pat. No. 3,781,429 (Partridge, "Method of Inhibiting Ulcerogenisis induced by Non-Steroidal Anti-Inflammatory Agents"), issued Dec. 25, 1973. Clinical reports of the reduction of gastrointestinal side effects from the concomitant administration of prostaglandins with NOSAC's are described by C. Johansson, et al., "Mucosal Protection by Prostaglandin E.sub.2 "), The Lancet, Feb. 10, 1979, p. 317, and M. M. Cohen, "Mucosal Protection by Prostaglandin E.sub.2 ", The Lancet, Dec. 9, 1978, p. 1253-1254.
Another method of preventing or treating certain gastrointestinal diseases, specifically gastric diseases, is by inhibition of gastric acid secretion. In situations where the integrity of the gastric mucosal barrier is compromised, gastric acid secretion can result in erosion of the epithelial cells with consequent inflammation and ulceration. Inhibition of such untoward gastric acid-induced effects can be achieved by either neutralization of the effects of the acid (e.g., antacid administration), or by administration of a pharmacological agent effective to inhibit gastric acid secretion.
One class of such agents effective to inhibit gastric acid secretion are the gastric antisecretory prostaglandins. These substances are known to be effective in the treatment and cure of gastric and duodenal ulcers as a result of the inhibition of gastric secretion. See U.S. Pat. No. 3,903,297 (Robert, "Method of Treatment and Prophylaxis of Gastric Hypersection and Gastric Duodenal Ulcers Using Prostaglandin Analogs"), issued Sept. 2, 1975 and Robert, "Antisecretory Property of Prostaglandins", Prostaglandin Symposium of the Worcester Foundation for Experimental Biology, 16-17 October 1967, Inter-Science, New York, 1978, p. 47. Another important class of antisecretory agents are the histamine H.sub.2 receptor antagonists, including metiamide and most especially cimetidine, N-cyano-N'-methyl-N"[2-[[(5-methyl-1H-imidazol-4-yl)methyl]thio]ethyl]guna nidine. See the Merck Index, 9th Edition, (APP-1 A-3) and Physicians' Desk Reference, 34th Edition, (1980), pages 1636-1641.
Accordingly, three classes of cytoprotective actions are known to affect beneficially gastrointestinal inflammatory diseases: (1) direct cytoprotective effects, such as those exhibited by the prostaglandins, (2) inhibitory effects on the untoward consequences of prostaglandin synthetase inhibition, e.g., such as are produced by NOSAC administration, and (3) inhibitory effects on the untoward effects of gastric acid secretion, such as are produced by antacids and gastric antisecretory agents such as prostaglandins and histamine H.sub.2 receptor antagonists. Although the first of these three effects (protection from non-gastric acid and non-NOSAC induced inflammatory diseases) is the only one which can unconditionally be referred to as a "cytoprotective" effect, nonetheless both direct cytoprotective effects and the protective effects of the inhibition of untoward NOSAC-induced effects are commonly known in the art as "cytoprotective". Accordingly, the term "cytoprotective effect", "cytoprotective action", and "cytoprotection" as used herein will refer both to direct cytoprotection (U.S. Pat. Nos. 4,083,998, 4,081,553, and 4,097,603) and inhibition of NOSAC-induced effects (U.S. Pat. Nos. 3,927,213 and 3,781,429), but not protection against gastric-acid induced inflammatory diseases.
Although the prostaglandins represent a class of agents which, in some cases, are both "cytoprotective" and inhibitors of gastric secretion, not all gastric antisecretory agents exhibit appreciable cytoprotective effects. Moreover, antacids which effectively neutralize gastric acid are not cytoprotective. Cimetidine, for example, is an example of a highly potent inhibitor of gastric secretion, which is devoid of appreciable cytoprotective effects. See A. Robert, "Cytoprotection Against Acidified Aspirin: Comparison of Prostaglandin, Cimetidine, and Probanthine", Gastroenterology 76:1227 (May 1979), and references cited therein indicating any apparent cytoprotective effects of cimetidine are related to its antisecretory property. See also Kauffman, G. L., et al., "Cimeditine Does Not Inhibit Indomethacin-Induced Small Bowel Ulceration in the Rat", Proc. of the Soc. Exp. Biol. Med. 161:512-4 (1979).
The present invention specifically relates to heterocyclylalkylsulfinylbenzimidazoles, heretofore known to be useful as gastric antisecretory agents and, therefore, useful in the treatment of gastric ulcers. See U.S. Pat. No. 4,045,563 and European Published Patent Application No. 0 005 129 (abstracted and published as Derwent Farmdoc CPI No. 79478B). For at least certain of these substituted benzimidazoles, the inhibition of gastric secretion is accomplished by direct action on the acid-secreting parietal cells of the stomach, specifically through inhibition of potassium ion-dependent APTase. See, for example, Lars Olbe, et al., "Properties of a New Class of Gastric Acid Inhibitors", Scand. J. Gastroenterol, 14:131-135 (1979, Supp 55).